As reviewed by L. J. Peters, in Cancer, 77, 2379 (1996), the concept of "treatment to tolerance" is deeply rooted in the practice of oncology. Because relatively few cancers can reliably be cured with chemotherapy and/or radiation therapy, the principle has evolved that treatment should be aimed at the maximum tolerated dose (MTD). Routinely, new treatment strategies undergo Phase I trials in which the MTD is established by dose escalation to the point at which an "acceptable" level of toxicity is encountered. Implicit in this approach is the assumption that the patients enrolled in the Phase I study are representative of the population with the disease, and that the probability of treatment toxicity is dose-related in a predictable way. Neither of these assumptions is true if the patient population is heterogeneous with regard to susceptibility to toxicity; and the MTD determined from a limited Phase I study cannot be assumed to have general applicability.
With chemotherapy, unlike radiotherapy, toxicity is mostly acute or cumulative, and since treatment is usually administered cyclically, the lack of a well-defined MTD can be partially circumvented by titrating the dose given to each patient to conform to his or her individual tolerance. Conversely, definitive radiation is given as a single course, and is dose-limited in the main by toxicities that develop after therapy is completed. Thus, any concept of MTD has to be based on probabilistic estimates of the risk of injury for the population as a whole.
Acute mucosal damage, such as damage to the intestine can be a major dose-limiting event in radiation therapy and chemotherapy, and has been extensively studied in the laboratory regarding the cellular mechanism of injury. Aspects of rapid cell turnover, distinct compartmentalization of damage, and known differentiation pathways of crypt cells in the murine and human intestine have been well studied. See, for example, C. S. Potten, Int. J. Radiat. Oncol. Biol. Phys., 58, 925 (1990). Treatment effect after cytotoxic chemotherapy or irradiation has been evaluated by apoptosis induction, and the classically by crypt colony assay. H. R. Withers et al., Int. J. Rad. Biol., 17, 261 (1970); A. C. Ruifok et al., Rad. Res., 149, 360 (1998). The former is a very sensitive method that may saturate at 1 Gy, and the latter has a threshold at doses of 8 to 9 Gy. See, C. S. Potten et al., Int. J. Rad. Biol., 65, 71 (1994); Withers et al., cited supra.
Functional disorders of the intestine including those created by ionizing irradiation can be measured by abnormalities in absorption of various nutrients including glucose, vitamin B12, D-xylose and bile acids. For example, see A. B. R. Thompson et al., Rad. Res., 107, 344 (1986). Most of these studies have been performed on rodents using either in vivo or in vitro perfusion techniques, and have limited clinical application (J. Overgaard et al., Radiother. Onc., 18, 71 (1990)). One of the earliest functional changes seen with irradiation of the gut is a disturbance of ATP-dependent transport of nutrients through the intestinal epithelial cells which include changes in the maximal velocity, the Michaelis constant and incremental changes in free energy (A. B. R. Thompson et al., J. Lab. Clin. Med., 102, 813 (1983)). The reduction in the active transport of glucose across the jejunal mucosa following irradiation has been tightly correlated with the epithelial surface area available for the absorption by P. J. Gunter-Smith, Rad. Res., 117, 419 (1989) and J. Overgaard et al., cited supra, and the authors suggested this could be used clinically to detect radiation damage to the intestine in relationship with epithelial cell loss.
Thus, a continuing need exists for new methods to assess treatment effects that are sensitive to cytotoxic treatment in clinically relevant dose ranges, that are noninvasive, and that could allow for repeated assessment in the same subject to understand the time course of cytotoxic insult.